Background Propofol is one of the most popular intravenous anesthetics used for induction and maintenance of anesthesia and sedation in and outside of the operating room. Its role is valuable especially for day-case surgeries, and with laryngeal mask airways. Pain on propofol injection still remains a common anesthetic problem. This study aimed at comparing the effectiveness of pretreatment with ondansetron, a common antiemetic agent, with lidocaine, the commonest drug/method for prevention of this pain.Materials and methods This study included 100 women, American Society of Anaesthesiologists physical status classification I–II, scheduled for gynecological surgery under general anesthesia and randomly categorized into two equal groups. Group I (group O) received 4-mg (2 ml) ondansetron, whereas group II (group L) received 40-mg (2 ml) lidocaine 2%, accompanied by manual venous occlusion for 1 min, and then 25% of the total induction dose of propofol (2.5 mg/kg) was initially injected through the same cannula, and patients were asked for pain rating using a four-point verbal rating scale.Results The incidence of pain was higher in group L than group O, with 17 (34%) patients versus 13 (26%) patients, respectively; however, both groups were still comparable (P>0.05). Three (6%) patients in group O versus four (8%) patients in group L complained of severe pain (P>0.05). Three (6%) patients in each group had moderate pain (P>0.05). Seven (14%) patients in group O versus 10 (20%) patients in group L experienced mild pain (P>0.05).Conclusion Both ondansetron and lidocaine were similarly effective pretreatment drugs for prevention of propofol-induced pain.

Pain on injection of propofol is a well-recognized adverse effect of this widely used anesthetic agent and an important cause of patient dissatisfaction [1]. The reported incidence of pain on propofol injection lies between 28 and 90% in adults during induction of anesthesia when a vein on the dorsum of the hand is used, and it may be severe [2],[3]. The incidence of pain in children ranges between 28 and 85%. There is no sex difference in the incidence of propofol injection pain [4]. The quality of pain is often described as extremely sharp, aching, or burning [5].

Many techniques have been used over the years to reduce the incidence and severity of such pain; however, their results are variable [3]. The most commonly studied technique is venous occlusion together with the use of various drugs such as lidocaine, antiemetics, nonsteroidal anti-inflammatory drugs, β-blockers, and opioids. In this category, pretreatment using lidocaine in conjunction with venous occlusion is the most effective intervention at preventing such pain [6].

Ondansetron is a specific 5-hydroxytryptamine (5-HT3) receptor antagonist. It has been reported that ondansetron produces numbness when injected under the skin and has local anesthetic effect that is ∼15 times more potent than lidocaine and probably explains its antiemetic action [7]. In practice, ondansetron is frequently administered as pretreatment medication to prevent postoperative nausea and vomiting.

The aim of this randomized double-blinded study is to detect effectiveness of ondansetron pretreatment administration in preventing pain of propofol injection and comparing its effect with that of lidocaine, which is the most common drug used for this purpose.

Materials and methods

This prospective double-blinded study was conducted after obtaining institutional ethical committee approval in Ain Shams University Maternity Hospital in the period from August 2016 to March 2017. It included 100 adult women of American Society of Anaesthesiologists physical status class I–II, aged between 20 and 50 years. Informed consent was taken from all. They fasted for 8 h before elective gynecological surgery under general anesthesia. The procedure was explained to patients during the preanesthetic visit and once again before propofol injection in the operation room.

Patients with psychological disease or communication problems; neurological diseases; previous allergic response to propofol, 5-HT3 receptor antagonists, or lidocaine; or received any analgesic or sedative within 24 h before surgery were excluded from the study.

Patients were randomly classified into two equal groups using computer-generated random numbers (50 in each group): group I (group O) received 4-mg (2 ml) ondansetron as pretreatment medication, and group II (group L) received 40 mg (2 ml) lidocaine 2% as pretreatment medication before intravenous administration of propofol as an induction agent. All drugs were freshly prepared by an anesthetic technician not involved in the study, and the investigator was blinded to the content of solution in syringes. No preteatment medication was given to any patient before the pretreatment injection.

In the operation theatre, heart rate, noninvasive arterial blood pressure, and peripheral O2 saturation were monitored in all patients; blood pressure cuff was applied to the opposite extremity of intravenous cannula. An 18-G cannula was intravenously inserted on the dorsum of the patient’s nondominant hand and normal saline solution was infused. A volume of 2 ml of a pretreatment drug was intravenously given to each patient over a period of 5 s, with manual occlusion of venous drainage at mid-forearm for 1 min by an assistant to allow for the action of pretreatment drugs to begin and enhance their local anesthetic effect [4]. After a minute, the occlusion was released, and induction of anesthesia was started with propofol (2.5 mg/kg). At first initial bolus, 25% of the total induction dose of propofol was given over 5 s. This small dose produces only a state of sleepiness (confusion) and does not interfere with patient response to pain whether verbal or behavioral.

Any sensation of pain during injection of propofol was rated by each patient 15 s after the initial bolus using a four-point verbal rating scale: 0=no pain (negative response to questioning), 1=mild pain (pain reported only in response to questioning without any behavioral signs), 2=moderate pain (pain reported in response to questioning accompanied by a behavioral sign or pain spontaneously reported without questioning), and 3=severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal or tears) [8]. A second anesthesiologist blinded to the study protocol and group allocation assessed and recorded the level of pain experienced by patients.

Thereafter, the rest (75%) of the induction dose of propofol was given together with fentanyl 1.5 μg/kg, and atracurium 0.5 mg/kg to facilitate endotracheal intubation. Anesthesia was maintained with sevoflurane in 100% oxygen under intermittent positive pressure ventilation.

Statistical analysis

Based on the literature, the incidence of pain on propofol injection was assumed as 80%, and 50% reduction in pain was considered clinically significant.

Sample size was calculated using the Power Analysis and sample size 11 software program, PASS 11 (version: 11.0.8; released on 2 December 2011; NCSS, LLC, Kaysville, Utah, USA). Sample size of 50 in each group achieved 80% power assuming type I error (α error=0.05) to detect a reduction in pain (which is the primary outcome measure) of 0.5. The proportion in group I (group O: ondansetron group) was assumed to be 0.50 under the null hypothesis and 0.80 under the alternative hypothesis.

The collected data were organized, tabulated, and statistically analyzed using IBM SPSS statistics for Windows version 20.0, released in 2011 (IBM Corp., Armonk, New York, USA). Quantitative and qualitative data were presented as mean±SD and numbers (percentage distribution), respectively. The results were statistically analyzed using unpaired Student’s t-test (for quantitative data) and χ2-test (for qualitative categorical data). P value if less than 0.05 was considered statistically significant.

Pain was experienced by 17 (34%) patients in group L compared with only 13 (26%) patients in group O (P>0.05; [Table 2]). A lower number of patients in group O complained of severe pain, three (6%) patients versus four (8%) patients in group L (P>0.05). The incidence of moderate pain was same in both the groups (three patients; 6% in each group), whereas the incidence of mild pain was less in group O than in group L: seven (14%) patients versus 10 (20%) patients, respectively (P>0.05; [Table 2]). No sense of pain or discomfort was felt by any patient during injection of the pretreatment drugs. In patients of both groups experiencing moderate to severe pain; their scores were 2–3 using verbal rating scale, transient rise in heart rate was noted without changes in arterial blood pressure.

Propofol is chemically a hindered phenol that is characteristically dissimilar to any other drugs used in anesthesia [4]. The underlying mechanism of pain on propofol injection is still not fully understood [9]. However, many explanations had been proposed for such pain, included endothelial irritation, osmolality differences, nonphysiological pH, and activation of mediators [10]. There are initial and delayed components of the pain. The initial component involves immediate stimulation of nociceptors and free nerve endings [11] and seems to be mainly related to the concentration of free drug within the aqueous phase of the emulsion [12]. The delayed component appears within half a minute. It is also suggested to result from interaction with nociceptors and free nerve endings [11], in addition to local vasodilatation and hyperpermeability of the area induced by bradykinin [13],[14] and possibly also prostaglandin E2 [13],[15].

Propofol has a higher incidence of pain on injection when compared with other intravenous anesthetic agents. The incidence with thiopental is ∼7%; with methohexital, it varies between 12 and 64%; and with etomidate, it varies between 24 and 68% [4]. Pain on propofol injection is greater than that after thiopental, equal to that with methohexital, and less than or equal to that with etomidate [16],[17].

The incidence of pain on propofol injection can be reduced by avoiding veins on the dorsum of hand, by using a large forearm vein probably by reducing contact between drug and endothelium, and by changing propofol formulation [6]. Cooling propofol to 4°C is another way to reduce pain possibly by delaying the activation of enzymatic cascade of pain mediators [18]. Diluting propofol with intralipid [10] and cutaneous application of eutectic mixture of local anesthetic cream before venepuncture have also been described to reduce such pain [19].

Pretreatment with small dose of propofol itself, ketamine, thiopentone, opiates, nonsteroidal anti-inflammatory drugs, esmolol/metoprolol, magnesium, a flash of light, clonidine/ephedrine combination, dexamethasone, and metoclopramide, all have been investigated to reduce pain on injection of propofol with variable results [6],[11],[20],[21].

Adding lidocaine to or giving it before injection of propofol is extensively administered; however, protection is not complete, as there is a failure rate between 13 and 44% [22],[23]. Metoclopramide has structural and physiochemical similarities with lidocaine [24] and possesses weak local anesthetic effect [25], and accordingly, it was similarly effective as lidocaine in reducing propofol injection pain [26].

Ondansetron possesses analgesic effect by its multifaceted actions as a 5-HT3 receptor antagonist, a Na channel blocker, and a mu-opioid agonist [7],[27]. Ondansetron pretreatment was successfully used to reduce the incidence of pain on injection of propofolin addition to its advantage of prevention of postoperative nausea and vomiting [28],[29].

In this study, the incidence of pain was comparable in both groups; it was 26% with ondansetron pretreatment (group O) versus 34% with lidocaine pretreatment (group L) using a dorsal hand vein in conjunction with manual venous occlusion at mid-forearm for 1 min. Pain was assessed 15 s after propofol injection because pain during propofol injection can be immediate or delayed, with the latter component having latency between 10 and 20 s [30]. Pain relief in both groups is mostly the result of a peripheral local anesthetic action of ondansetron [7] and lidocaine, which attenuated the afferent pain pathway rather than a central analgesic effect.Coinciding with the result of this study, the study by Piper et al. [31] stated there was insignificant difference in the incidence of propofol injection pain between dolasetron (a 5-HT3 receptor antagonist) and lidocaine, and also the study by Singh et al. [32] study reported that ramosetron (a 5-HT3 receptor antagonist) and lidocaine were equally effective in reducing pain of propofol injection.

Furthermore, in this study, there were comparable incidences of moderate pain (only 6% in each group) and severe pain (only 6% in group O vs. 8% in group L) in both groups. This proves further the effectiveness of both drugs in reducing such pain. This result was close to that of Singh et al. [32] study, in which 5% in each group, ramosetron and lidocaine groups, experienced moderate pain, and 5% in each group experienced severe pain on propofol injection.

It is difficult to explain why the difference between the proposed 15 times more potent local anesthetic effect of ondansetron compared with lidocaine [7] was not reflected in the results of this study, as there was comparable incidence of pain in both groups. Probably, the interaction between local anesthetics and Na channels plays some role and has an effect on potency, and the net effect could be the result of factors like the drug dose, drug concentration, Na channel state, rate of onset, and offset of action.

In this study, venous occlusion at mid-forearm was manually done. Thus, the degree of occlusion possibly varies from person to person. This represents limitation of the study, and it could be avoided by applying a tourniquet with constant pressure.

Conclusion

Pretreatment with ondansetron together with venous occlusion for 1 min is similarly effective as pretreatment with lidocaine in addition to venous occlusion for 1 min for prevention of propofol-induced pain. Ondansetron has the added advantage of prevention of postoperative nausea and vomiting with a single agent that may be useful especially in elective surgery.

5.Macario A, Weinger M, Truong P, Lee M. Which clinical anesthesia outcomes are both common and important to avoid? The perspective of a panel of expert anesthesiologists. Anesth Analg 1999; 88:1085–1091.